2-231925549-G-T

Position:

• chr2-231925549-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024409.4(NPPC):​c.257C>A​(p.Ala86Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPPC NM_024409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

Genes affected

NPPC (HGNC:7941): (natriuretic peptide C) This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the cardiac natriuretic peptides CNP-53, CNP-29 and CNP-22, which belong to the natriuretic family of peptides. The encoded peptides exhibit vasorelaxation activity in laboratory animals and elevated levels of CNP-22 have been observed in the plasma of chronic heart failure patients. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40048057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPC	NM_024409.4	c.257C>A	p.Ala86Asp	missense_variant	2/3	ENST00000409852.2	NP_077720.1
NPPC	XM_011511245.4	c.257C>A	p.Ala86Asp	missense_variant	2/3		XP_011509547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPC	ENST00000409852.2	c.257C>A	p.Ala86Asp	missense_variant	2/3	3	NM_024409.4	ENSP00000387159	P1
NPPC	ENST00000295440.2	c.257C>A	p.Ala86Asp	missense_variant	2/2	1		ENSP00000295440	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.257C>A (p.A86D) alteration is located in exon 1 (coding exon 1) of the NPPC gene. This alteration results from a C to A substitution at nucleotide position 257, causing the alanine (A) at amino acid position 86 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.014
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.56	.;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.088
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.15	B;B
Vest4		0.44
MutPred		0.51		Loss of MoRF binding (P = 0.0731);Loss of MoRF binding (P = 0.0731);
MVP		0.70
MPC		0.73
ClinPred		0.93	D
GERP RS		3.2
Varity_R		0.32
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-232790259;